A Yellow Flower With Jaundice Power: Liver Injury Attributed to Greater Celandine

ABSTRACT Greater celandine (Chelidonium majus) leaf extracts have been used for centuries as a natural remedy for various gastrointestinal symptoms. Greater celandine is associated with several case reports of hepatotoxicity, mainly from Europe. No cases from the United States have been identified. We present a case of acute hepatitis from greater celandine in the United States in a 72-year-old man taking this herbal supplement for nausea. In patients presenting with acute liver injury, gastroenterologists should be aware of this herb and reminded to assess for herbal and dietary supplement hepatotoxicity, especially in those remedies used to treat common gastrointestinal symptoms.


INTRODUCTION
Idiosyncratic drug-induced liver injury (DILI) accounts for approximately 13% of acute liver injuries (ALI). 1,2The incidence of herbal and dietary supplement (HDS)-related DILI has nearly tripled in the United States since 2004. 3Even in the absence of alternative etiologies of ALI, diagnosing DILI is challenging in patients with polypharmacy and other confounding variables.
Greater celandine (Chelidonium majus) is a flowering plant in the Poppy family (Papaveraceae) indigenous to Eurasia 4 (Figure 1).Greater celandine leaf extracts contain several biologically active alkaloids with reported antispasmodic and mildly sedating properties. 4Greater celandine has been used in homeopathy for centuries for gastrointestinal symptoms including nausea, dyspepsia, and biliary colic. 1,4,5Case reports, primarily in Europe, describe greater celandine causing idiosyncratic hepatotoxicity. 4,5We present to our knowledge the first reported case of DILI attributed to greater celandine in the United States

CASE REPORT
A 72-year-old man with diabetes, diabetic neuropathy, hypertension, hyperlipidemia, irritable bowel syndrome, and chronic pain presented to the hospital with several days of malaise, dark urine, and jaundice.He had no history of liver disease, abnormal liver tests, alcohol, or substance use.His home medications included acetaminophen-hydrocodone, aspirin, atorvastatin, glipizide, insulin glargine, and metformin (Table 1).The only new prescribed medication was liraglutide, which was started 2 weeks before admission.Three months before admission, he started using several HDS for chronic abdominal pain and nausea including Nux vomica, Arnica montana, and greater celandine, 5 pellets 3 times a day (approximately 6.6 mg/d).His chronic gastrointestinal upset was attributed to irritable bowel syndrome as prior endoscopy, and abdominal imaging were normal.
On presentation, vital signs were within normal limits and physical examination was unremarkable except for jaundice.There was no evidence of hepatic encephalopathy, hepatosplenomegaly, or ascites.Serum total bilirubin was 12.3 mg/dL, alkaline phosphatase 507 U/L, alanine aminotransferase 974 U/L, and aspartate aminotransferase 1,119 U/L consistent with hepatocellular liver injury (R value 5.8).Broad workup including viral and autoimmune hepatitis serologies was negative (Table 2).Abdominal ultrasound and computed tomography were normal, ruling out obstruction.Liver biopsy showed hepatitis, lymphocytic inflammation with eosinophils, hepatocyte necrosis, grade 3 activity, stage 1 fibrosis, and mild fatty changes (Figure 2).DILI was the suspected etiology of transaminase elevation, and all HDS products were discontinued, none were restarted.Liver tests improved, and he was discharged.Within 2 months of hospitalization, his liver tests normalized and remained normal at the 8-month follow-up (Figure 3).

DISCUSSION
HDS are widely used yet often overlooked and underreported.The incidence of HDS-related DILI in the United States almost tripled from 7% (2004) to 19% (2012), and HDS sales in the United States increased by 17.3% in 2020. 3,6A prospective study by the Drug-Induced Liver Injury Network found 15.5% of DILI were caused by HDS. 7 As HDS use increases, providers must be aware of commonly used herbs and potential toxicities.
Greater celandine is available in the United States and advertised as a safe and effective antiemetic for adults and children. 8The leaf extracts of greater celandine contain over 20 biologically active isoquinoline alkaloids including benzophenanthridines, protoberberines, and hydroxycinnamic acid derivatives, although the exact chemical(s) responsible for hepatotoxicity is unknown. 4,5,9hrough an unclear mechanism, these alkaloids have antispasmodic and mildly sedating properties and have been shown in animal studies to increase bile flow. 4,5,9Greater celandine is used for many gastrointestinal symptoms such as nausea, dyspepsia, and gallbladder disease. 4,5Alternative uses include asthma, bronchitis, skin conditions, and weight loss. 4eater celandine is a known hepatotoxin (likelihood score B) with many idiosyncratic features described in more than 40 case reports. 4,5As greater celandine is native to Eurasia, nearly all cases in the medical literature are from Europe, no cases have been described in the United States 4,5 Dosing associated with greater celandine DILI is difficult to determine as HDS are not strictly regulated, although a clinical review of 43 cases found the average daily dose was 10 mg. 5 Clinically greater celandine associated DILI resembles acute hepatitis with jaundice and severely elevated transaminases in a hepatocellular pattern. 4,5Liver histology typically shows hepatitis and necrosis, the stage 1 fibrosis in this case was likely from prevalent hepatic steatosis. 5Hepatotoxicity occurs within 1-6 months of taking the herb and rapidly resolves without intervention after the product is discontinued. 4,5Autoantibodies are not typically present but can be in low levels, although clinically greater celandine DILI does not resemble autoimmune hepatitis or require corticosteroids. 4This patient started using greater celandine approximately 6.6 mg/d 3 months before ALI and his clinical course, and liver tests and biopsy resembles other described cases of greater celandine DILI from Europe. 4,5ill, establishing causality for DILI in this case was challenging due to many confounding factors.He recently started liraglutide, was taking known hepatotoxic medications, and used several HDS (Table 1).Despite the temporal association of liraglutide initiation and liver injury, DILI from glucagon-like  peptide 1 agonists is rare (likelihood score E). [10][11][12][13] In large clinical trials, there was no significant difference in transaminase elevation between liraglutide and placebo. 101][12][13] One case reported liraglutideassociated autoimmune hepatitis that did not resolve with discontinuation of liraglutide and required long-term corticosteroids. 13Otherwise, there are 2 published cases of liraglutideassociated DILI that demonstrated hepatocellular injury and resolved after discontinuing the drug. 11,12The home hepatotoxic medications with likelihood score A must be taken in high doses to cause DILI, and he was not taking such doses (Table 1).
Metformin (likelihood B) can causes minor transaminase elevation but rarely causes clinically apparent ALI. 14 Importantly, he tolerated all home medications for years with no history of elevated liver tests or dose changes, and these medications were continued as liver tests improved, rendering these agents as unlikely causes of his ALI.Nux vomica and Arnica montana have not been implicated in causing liver injury. 15,16Therefore, the most likely product responsible for this patient's ALI is greater celandine.This case was enrolled in the Drug-Induced Liver Injury Network and adjudicated by the Causality Committee to be highly likely DILI from greater celandine with a Roussel Uclaf Causality Assessment Method score of 9 indicating greater celandine DILI is highly probable.
This case describes greater celandine associated hepatotoxicity with idiosyncratic features consistent with other described cases

DISCLOSURES
Author contributions: S. Power: writing and editing.AS Barritt: writing editing and supervision.A. Sidney Barritt IV is the article guarantor.

Figure 2 .
Figure 2. Liver biopsy.(A) Hematoxylin and eosin (H&E) stain at 23 shows intact hepatic architecture with mild fatty change and evidence of variably dense inflammation within lobules and portal tracts.(B) H&E stain at 103 shows portal tract containing lymphocytic inflammation with some eosinophils and evidence of interface hepatitis.(C) H&E stain at 203 shows lobular lymphocytic inflammation with eosinophils and hepatocyte necrosis.

Table 1 .
Patient's medications and supplements a Likelihood of DILI: A 5 well known, .50cases including case series, characteristic signature; B 5 known or highly likely, 12-50 cases including small case series, characteristic signature; C 5 probably linked, ,12 cases without case series; D 5 possible, ,3 case reports; E 5 not believed or unlikely, no evidence/unconvincing single case reports; X 5 unknown.

Table 2 .
Liver tests trend and serologic evaluation of acute liver injury ALT, alanine aminotransferase; AST, aspartate aminotransferase.INR, international normalized ratio; IgM, immunogloblulin M; IgG, immunoglobulin G ACG Case Reports Journal / Volume 11 acgcasereports.com3 in Europe.Also highlighted are the challenges of determining causality for DILI and consequently the importance of thorough medication history including specific HDS and homeopathic remedies.Gastroenterologists should be aware that greater celandine is available in the United States and used for common gastrointestinal symptoms to provide counseling on the potential risks of this herb.